Cargando…

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is p...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Junghee, Kim, Yunha, Liu, Tian, Hwang, Yu Jin, Hyeon, Seung Jae, Im, Hyeonjoo, Lee, Kyungeun, Alvarez, Victor E., McKee, Ann C., Um, Soo‐Jong, Hur, Manwook, Mook‐Jung, Inhee, Kowall, Neil W., Ryu, Hoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771400/
https://www.ncbi.nlm.nih.gov/pubmed/29130578
http://dx.doi.org/10.1111/acel.12679
_version_ 1783293261649018880
author Lee, Junghee
Kim, Yunha
Liu, Tian
Hwang, Yu Jin
Hyeon, Seung Jae
Im, Hyeonjoo
Lee, Kyungeun
Alvarez, Victor E.
McKee, Ann C.
Um, Soo‐Jong
Hur, Manwook
Mook‐Jung, Inhee
Kowall, Neil W.
Ryu, Hoon
author_facet Lee, Junghee
Kim, Yunha
Liu, Tian
Hwang, Yu Jin
Hyeon, Seung Jae
Im, Hyeonjoo
Lee, Kyungeun
Alvarez, Victor E.
McKee, Ann C.
Um, Soo‐Jong
Hur, Manwook
Mook‐Jung, Inhee
Kowall, Neil W.
Ryu, Hoon
author_sort Lee, Junghee
collection PubMed
description Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.
format Online
Article
Text
id pubmed-5771400
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-57714002018-02-01 SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease Lee, Junghee Kim, Yunha Liu, Tian Hwang, Yu Jin Hyeon, Seung Jae Im, Hyeonjoo Lee, Kyungeun Alvarez, Victor E. McKee, Ann C. Um, Soo‐Jong Hur, Manwook Mook‐Jung, Inhee Kowall, Neil W. Ryu, Hoon Aging Cell Original Articles Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD. John Wiley and Sons Inc. 2017-11-11 2018-02 /pmc/articles/PMC5771400/ /pubmed/29130578 http://dx.doi.org/10.1111/acel.12679 Text en © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Lee, Junghee
Kim, Yunha
Liu, Tian
Hwang, Yu Jin
Hyeon, Seung Jae
Im, Hyeonjoo
Lee, Kyungeun
Alvarez, Victor E.
McKee, Ann C.
Um, Soo‐Jong
Hur, Manwook
Mook‐Jung, Inhee
Kowall, Neil W.
Ryu, Hoon
SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
title SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
title_full SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
title_fullStr SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
title_full_unstemmed SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
title_short SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
title_sort sirt3 deregulation is linked to mitochondrial dysfunction in alzheimer's disease
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771400/
https://www.ncbi.nlm.nih.gov/pubmed/29130578
http://dx.doi.org/10.1111/acel.12679
work_keys_str_mv AT leejunghee sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT kimyunha sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT liutian sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT hwangyujin sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT hyeonseungjae sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT imhyeonjoo sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT leekyungeun sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT alvarezvictore sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT mckeeannc sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT umsoojong sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT hurmanwook sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT mookjunginhee sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT kowallneilw sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease
AT ryuhoon sirt3deregulationislinkedtomitochondrialdysfunctioninalzheimersdisease